Thomas Raphael Meinel, MD
Sharma M, Hart RG, Smith EE, Bosch J, Eikelboom JW, Connolly SJ, Dyal L, Reeh KW, Casanova A, Diaz R, et al. Rivaroxaban for Prevention of Covert Brain Infarcts and Cognitive Decline: The COMPASS MRI Substudy. Stroke. 2020;51:2901–2909.
Covert brain infarctions (CBI) are multiple times more frequent than manifest ischemic stroke.1 However, data on preventive strategies to reduce accrual of CBI is almost non-existent. Sharma et al. aimed to investigate whether the combination therapy of rivaroxaban (2.5mg twice daily) plus aspirin (100mg once daily) or rivaroxaban (5mg twice daily) was superior to aspirin (100mg once daily) in the prevention of CBI in patients with stable atherosclerotic vascular disease.
For this purpose, the authors conducted the COMPASS-MIND substudy of the COMPASS trial including patients with coronary artery disease, peripheral arterial disease, or both. The exclusion criteria were high bleeding risk; ischemic stroke within 1 month or any history of hemorrhagic or lacunar stroke; severe heart failure; advanced kidney disease; or the need for other antithrombotic regimens. Of note, only 6.4% of the trial population had prior manifest cerebrovascular disease.
1445 patients underwent a baseline and follow-up MRI with a mean follow-up interval of two years. The MRI protocol was somewhat heterogeneous, but included standard sequences reflecting clinical practice. CBI were defined according to the STRIVE2 criteria, but included also cortical lesions and subcortical lesions larger than 15mm. The primary outcome was occurrence of incident CBI on follow-up MRI.
The authors found that 34% of participants had CBI at baseline. Numerically, the 481 participants assigned to rivaroxaban plus aspirin had the lowest rate of incident CBI (2.7%) as compared to 477 patients with rivaroxaban monotherapy (3.6%) and 487 patients with aspirin monotherapy (3.5%). However, this reduction did not reach significance (odds ratio 0.77, 95% CI 0.37–1.60) for the comparison of the combination therapy with aspirin. Nevertheless, the estimate was compatible with the overall reduction of clinical outcome events in the main trial. Interestingly, 28/47 (60%) of incident CBI were of a non-lacunar phenotype, and although the confidence intervals are wide, this phenotype seemed to be best reduced by anticoagulation.
This study once again shows that CBI occur roughly 4 to 5 times more frequently than manifest stroke, and incorporation of CBI into clinical trials is feasible and could improve the efficiency of future trials of stroke prevention. The pathophysiology of incident CBI is diverse and includes small-vessel disease, as well as embolic sources.3 An adjusted comparison between those with and without CBI at baseline might have been informative regarding a potential benefit of antiplatelet and/or anticoagulation therapy in the prevention of CBI according to CBI phenotypes.4
Of course, because of the benefit in the main COMPASS trial, the combination therapy should be used regardless of a presumed benefit for accrual of CBI. The main question, however, remains in those patients that do not fulfill the COMPASS inclusion criteria whether any antithrombotic therapy can prevent CBI, especially in those patients with incidentally discovered CBI. Further research needs to clarify whether phenotypes of CBI could identify candidates that benefit the most from specific preventive strategies such as antiplatelet therapy, anticoagulation, more aggressive antihypertensive therapy or lipid lowering treatment.
1. Vermeer SE, Longstreth WT, Koudstaal PJ. Silent brain infarcts: a systematic review. Lancet Neurol. 2007;6:611–619.
2. Wardlaw JM, Smith EE, Biessels GJ, Cordonnier C, Fazekas F, Frayne R, Lindley RI, O’Brien JT, Barkhof F, Benavente OR, et al. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol. 2013;12:822–838.
3. Meinel TR, Kaesmacher J, Roten L, Fischer U. Covert Brain Infarction: Towards Precision Medicine in Research, Diagnosis, and Therapy for a Silent Pandemic. Stroke. 2020;51:2597–2606.
4. Fanning JP, Wesley AJ, Wong AA, Fraser JF. Emerging spectra of silent brain infarction. Stroke. 2014;45:3461–3471.